We have identified regulatory differences between circulating monocytes and spleen macrophages. At concentrations up to 30%, monocytes promoted T cell proliferation, but suppressed this proliferation at higher concentrations. Spleen macrophages had only a positive regulatory role at up to a concentration of 50%. Alveolar macrophages had regulatory effects comparable to those of blood monocytes. We decided that emphasis has generally been directed, when studying lymphocyte regulation, to the terminal expression of lymphocyte responses. We acquired the capacity to measure cellular ornithine decarboxylase (ODC) because it catalyzes a crucial regulatory step in polyamine synthesis when it precedes the expression of lymphocyte responses. We found that mitogen and activation of T-lymphocyte ODC correlated well with [3H]-thymidine incorporation. Both parameters required monocyte participation. This participation could, however, be replaced by supernatants or fractions rich in interleukin-1 or interleukin-2. Interleukin-1 was derived from monocyte and macrophage cell line cultures, whereas interleukin-2 was derived from human T lymphocytes. These positive regulatory effects of monocytes and mediators upon ODC activation and [3H]-thymidine incor-poration are inhibited by cyclosporin A. We are presently seeing if high concentrations of monocytes suppress ODC activation as they do [3H]-thymidine incorporation. If this proves true, then we will examine the effects of high concentrations of monocyte-derived mediators upon early and terminal T-cell responses.